Humans possess limited potential for regenerating lost or severely damaged tissue. As a result, many important human diseases are the direct result of irreversible tissue damage. While most human tissues do not regenerate, many animals are capable of replacing missing or damaged tissues. Elucidating the molecular mechanisms that regulate animal regeneration may lead to novel treatment strategies for people living with degenerative diseases. The nervous system has been widely recognized as an important regulator of regeneration in a variety of animals, but few studies have identified the specific neural signals that influence this process. Neuropeptides are secreted peptide hormones and represent the most diverse class of signaling molecules in metazoans. Previous studies of planarians have suggested that neuropeptides may influence regeneration, yet little is known about the diversity and types of neuropeptides that are present in flatworms. To test the hypothesis that neuropeptides influence regeneration, bioinformatic and biochemical approaches will be used to identify neuropeptide prohormone genes in the experimentally tractable planarian Schmidtea mediterranea. The expression patterns of these genes will be determined by whole-mount in situ hybridization and the role of these genes in the regulation of stem cells and regeneration will be determined by RNA interference. These studies will be an important test of the hypothesis that neuropeptides are important for regeneration and will provide essential groundwork for future studies into the role of peptide hormones in animal biology. Humans do not possess robust mechanisms to regenerate missing or damaged tissues and organs. The planarian Schmidtea mediterranea can regenerate every tissue in its body including its intestine, reproductive organs and brain. These studies aim to identify molecules important for the regeneration of S. mediterranea tissues.